DESCRIPTION: (Adapted from the application) The molecular mechanisms which regulate human hematopoietic stem/progenitor cells underlie normal blood-formation as well as dysplastic or leukemic disease states. Much is known about the physical and functional properties of human stem/progenitor cells. However, there is little information which defines the exact molecular mechanisms of stem cell regulatory circuitry and pathways. The fundamental hypothesis is that stem/progenitor cell regulation is mediated at least in part, by panels of gene products expressed specifically in these cells. In this proposal a comprehensive strategy is developed to identify and characterize potential novel biological regulators and other molecules present specifically in the most primitive members of the human stem/progenitor cell hierarchy. The overall approach encompasses in-depth gene-expression screens as well as functional assays and genetic-selections designed to identify novel molecular components of various processes which play crucial roles in the biology of the stem cell. One feature of the proposed strategy is that it interfaces a number of state-of-the-art molecular and functional experimental designs with sophisticated bioinformatic analysis. It will thus be possible to draw upon existing biological knowledge obtained from a wide range of vertebrate as well as invertebrate stem cell and developmental systems. An ultimate goal of the proposed studies is to define an extensive molecular phenotype of human stem cells and to shed light on the functional role(s) of individual molecules. A molecular gene-expression profile of human stem cells will provide a necessary framework within which to explore the mechanisms underlying stem cell behavior.